As a comprehensive interdisciplinary group of synthetic chemists, biochemists, biophysical chemists and virologists, our goals are to develop novel nonnucleoside compounds as therapeutic agents against the human immunodeficiency virus (HIV). In the last two years we have tested approximately 700 compounds. We have discovered two, tetrakis (4- sulfonatophenyl) porphyrin and sulfonated tetrakis (3-hydroxyphenyl) porphyrin, with EC50(s) vs. HIV-1 (strain LAV in PBMC) of less than 0.1 (mu)M and therapeutic ratios of greater than 100 in both PBMC and Vero cells. In addition, we have found approximately 10 other compounds with EC50(s) of less than 1 (mu)M and similar therapeutic ratios. Different classes of compounds have different activities: reverse transcriptase inhibition, syncytia inhibition and nucleic acid interaction are the dominant mechanisms of pharmacological activity of the compounds studied by the GEVA group. We propose to continue the development of porphyrins, phthalocyanines, metal chelates of porphyrins and phthalocyanines, heteropolyarenes, aryl diimides and aryl diamidines. Our synthetic goals for new drug candidates are designed on the basis of our results to date and structure-activity relationships which we are developing using QSAR and other methods. Our biophysical/pharmacological goals are to probe the mechanisms of action of these compounds. In addition , we propose a new drug design strategy based on RNA-specific organic repressors (RASORS). These are bifunctional molecules that have an RNA duplex recognition (binding) unit and an RNA bulge base(s), loop or base pair mismatch binding unit; they will be designed to interact with specific areas of the HIV genetic sequence. Our preclinical goals are to evaluate the new compounds in a rational progression starting with in vitro screens and including biophysical, biochemical, pharmacological and toxicological investigations, concluding with in vivo assessments of drug efficacy and toxicity in mouse models. Our group will be able to provide a comprehensive approach to developing new, effective anti-HIV agents by synthesis of new compounds, by determination of anti-viral activity in cell culture and in mouse models, and by biochemical and pharmacological evaluation of the effects of these compounds on both the host and the virus.